Optimised preparations of highly adaptable aggregates

Abstract

The present invention describes improved compositions comprising aggregates having a higher adaptability, or deformability, owing to the inclusion of certain hydrophilic additives, including suitable organic ionic compounds. The disclosed compositions demonstrate superior adaptability and stability over otherwise similar compositions lacking the disclosed additives. The invention furthermore provides methods for manufacturing said aggregate preparations, wherein the resulting preparations are useful for applications such as receiving an aggregate payload with active ingredients, for biological agent delivery, and for a noninvasive targeted treatment of localised body regions at or below the application site of said aggregates.

1 . A composition comprising adaptable vesicular aggregates characterized by:
 at least one amphipat that forms adaptable vesicular aggregates with at least one amphipatic lipid bilayer in a polar fluid; and   at least one water-soluble additive with at least one C-atom and a tendency to accumulate near the aggregate surface to thereby improve at least one aggregate property, wherein said additive molecule provides:
 at least a 20% faster reduction of the average aggregate size under an external stress, wherein said aggregate size-reduction is reflected in a corresponding turbidity decrease; or 
 at least a 20% greater ability of the aggregate to cross a constriction that is at least 50% narrower than the average aggregate diameter; 
 compared to an adaptable vesicular aggregate lacking said additive. 
   
     
     
         2 . The composition of  claim 1 ,
 wherein the at least one water-soluble additive with at least one C-atom further comprises a net opposite charge to the charge of each of the at least second amphipat, and   wherein a second amphipat of the adaptable vesicular aggregate has an affinity for said aggregate and imparts a net charge on the aggregate surface.   
     
     
         3 . A composition comprising adaptable bilayer vesicle aggregates characterized by:
 wherein the at least one water-soluble additive with at least one C-atom further has an affinity for water, and   wherein said additive has a tendency to accumulate near the aggregate surface and thus to expand or partially destabilise the bilayer, and   wherein the at least one amphipat has about 12 or about 18 carbon atoms per fluid hydrophobic chain, each having an average area per chain (Ac) in a monolayer or bilayer of between about 0.35 nm 2  and about 0.55 nm 2 .   
     
     
         4 . A composition according to  claim 1 , wherein the adaptable vesicular aggregates further comprises:
 at least one polar fluid; and   at least one water-soluble additive with at least one charge; and   at least one amphipat having at least one fluid, hydrophobic segment with nC carbon atoms, preferably about 5nC/24 to about 8.5nC/24 polarity units per hydrophobic segment, wherein said hydrophobic segment is attached to at least one hydrophilic headgroup in the at least one amphipat, and
 wherein said at least one amphipat may be supplemented with one or more additional amphipats such that the total sum of all polarity units on all amphipats is about 8.5nC/24. 
   
     
     
         5 . A composition according to  claim 4 , wherein the at least one amphipat has at least one net charge. 
     
     
         6 . A composition according to  claim 1 , wherein the water-soluble and aggregate-improving additive has an octanol-water or aggregate-water distribution ratio of about −1±2. 
     
     
         7 . A composition according to  claim 1 , wherein the water-soluble and aggregate-improving additive is used at a total concentration of between about 5 mM and about 600 mM. 
     
     
         8 . A composition according to  claim 1 , wherein the total dry mass of aggregate forming components is between 0.05 wt.-% and 40 wt.-% 
     
     
         9 . A composition according to  claim 1 , wherein the composition pH and/or the pH prevailing at a site of application of said composition provides at least 20% ionisation of the aggregates or of the additive itself, and preferably of both. 
     
     
         10 . A composition according to  claim 9 , wherein the composition pH is in the range between about pH≦(pK a,mem +0.5) and around pH≦(pK a,mem −1.5) for aggregates with a positively charged surface, and between about pH≧(pK a,mem −0.5) and around pH≧(pK a,mem +1.5) for aggregates with a negatively charged surface. 
     
     
         11 . A composition according to  claim 1 , wherein the average aggregate diameter is between 20 nm and 1 μm. 
     
     
         12 . A composition according to  claim 1 , wherein the at least one amphipat is characterized by:
 one or more hydrophobic segments acting together as hydrophobic anchors that are directly or indirectly attached to at least one hydrophilic headgroup, wherein the direct attachment can be by a fatty chain ether, ester or amide linkage and wherein the indirect attachment can be by a sorbitane-, glycerol-, or oligooxyethylene-mediated fatty-conjugate with an oligomer or a polymer of a polyalcohol or a sugar, or a sugar oligomer, or its chemically stable lactone linkage; or   a linear or branched fatty chain ester, ether, amide or sphingoside having a phospho-headgroup or sulpho-headgroup or   a fatty phosphonate or sulphonate, glycerophosphocholine, glycerophosphodimethylethanolamine, glycerophosphoserine, glycerophosphoglycerol, glycerophosphomethyl- or -ethyl-ester or glycerophosphate and glycerosulphate; or   a betaine or sulphobetaine, a fatty dimethyl-ammonio]-1-alkane sulphonic, -phosphonic, or -acetic acid; or   a fatty secondary, (di)fatty ternary or quaternary amine, a (di)fatty amino or imino acid or any of its suitable derivatives; or   a fatty amine-oxide.   
     
     
         13 . A composition according to  claim 1 , wherein the hydrophobic segment on the amphipat has between about 8 and about 24 C-atoms. 
     
     
         14 . A composition according to  claim 1 , wherein the composition is associated with at least one pharmaceutical agent. 
     
     
         15 . A composition according to  claim 14 , wherein the at least one pharmaceutical agent is a drug useful for treating the digestive system, the cardiovascular system, the central nervous system, pain, musculo-skeletal disorders, the eye, the ear, nose, and oropharynx, the respiratory system, endocrine problems, the reproductive system or urinary system, the skin, infections and infestations, the immune system, allergic disorders, neoplastic disorders, or a drug for use in obstetrics and gynecology or for purposes of nutrition, contraception or diagnostic applications. 
     
     
         16 . A composition according to  claim 14 , wherein the pharmaceutical agent is used for treating a skin condition. 
     
     
         17 . A composition according to  claim 14 , wherein the pharmaceutical agent is an NSAID including ketoprofen, ketorolac, indomethacin, diclofenac, naprofen, ibuprofen, etoricoxib, celecoxib, rofecoxib, valdecoxib, meloxicam and piroxicam. 
     
     
         18 . A composition according to  claim 14 , wherein the pharmaceutical agent is an antimycotic agent including allylamines, such as butenafine, naftifine, or terbinafine, candicin, imidazoles, such as bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, or miconazole plus omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, triazoles, such as fluconazole, isavuconazole, or itraconazole plus posaconazole, ravuconazole, voriconazole, terconazole, amorolfine, griseofulvin, amphotericin B, filipin, hamycin, natamycin, nystatin, rimocidin, or abafungin. 
     
     
         19 . A composition according to  claim 1 , wherein the at least one water soluble additive is a linear or a branched, at least partially ionised fatty acid or an organic, at least partially ionised, base that in either case carries from about 2 to about 7 C-atoms per charged group plus about 1.5-2.5 more C-atoms per every extra charged residue and every extra uncharged polar group, such as an oxo- or hydroxy-group, in the additive, and about 1-2 C-atoms less per each apolar group, e.g. a halide atom, in the additive. 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . A method of preparing the composition comprising adaptable vesicular aggregates according to  claim 3 , comprising:
 selecting the at least one amphipat to have a molar ratio in the range of 0.1% to 50% with the at least one additive,   wherein said molar ratio is between 0.5% and 25% for additives that decrease the average area per hydrophobic chain of the amphipat, and   wherein said molar ratio is between 25% and 250% for additives that increase the average area per chain.   
     
     
         23 . (canceled)